Certain pyrimido (4, 5-b) indoles and intermediates employed in their preparation



United States Patent 3,414,574 CERTAIN PYRIMIDO(4,5-b)INDOLES AND INTERMEDIATES EMPLOYED IN THEIR PREPARATION Albert J. Frey, Essex Fells, Goetz E. Hardtrnann, Florham Park, and Hans Ott, Convent Station, N.J., assignors to Sandoz Inc., Hanover, NJ.

No Drawing. Filed Apr. 21, 1967, Ser. No. 632,552 4 Claims. (Cl. 260256.4)

ABSTRACT OF THE DISCLOSURE This invention relates to pyrimido[4,5-b]indoles, and more particularly to 3-amido-3,4-dihydro-4-oxo-pyrimido [4,5-b]indoles and salts thereof and a process for the preparation thereof. The invention also relates to intermediates in the preparation of said compounds and a process for preparation of said intermediates. The 3- amido-3,4-dihydro-4-oxo-pyrimido[4,5-b1indoles of this invention may be represented structurally as follows:

0 5 H H 0 REE J 2 R N N/ 2 I 8 l wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy; and

R is a member selected from the group consisting of a hydrogen atom, and linear alkyl having from I to 3 atoms, i.e., methyl, ethyl and propyl.

Compounds I are obtained according to the procedure of the folliwing reaction scheme wherein R and R are as defined above and R is lower linear alkyl, e.g., having from 1 to 6 carbon atoms:

According to the reaction scheme, Step a involves the 3,414,574 Patented Dec. 3, 1968 ice preparation of a Compound III, i.e., a hydrazide, from a Compound II, i.e., a Z-aminoindol-3-carboxylic acid lower linear alkyl ester, in a conventional manner. It is preferred to prepare the Compound III by heating a Compound II in a large excess of anhydrous hydrazine, e.g., 5 to 20 fold by weight, under reflux. If desired the reaction may be carried out in a suitable solvent, e.g., toluene, using from 1 to 2 molar equivalents of hydrazine and at to 120.

Step b is a cyclization of the Compound III to the corresponding Compound I, which is effected by heating at from to boiling, preferably by refluxing, a Compound III in a large excess, e.g., 5 to 40 fold by weight, of a Compound IV, which is a lower linear fatty acid having from 1 to4 carbon atoms, i.e., formic acid, acetic acid, propionic acid or butyric acid. If desired, the cyclization can be carried out in a suitable solvent, e.g., xylene, using from 2 to 4 equivalents of the Compound IV at temperatures of from 90 to the boiling point of the Compound IV.

Compounds II may be obtained according to the procedure described by C. A. Grob and O. Weissbach in Helvetica Chimica Acta, volume 44, pages 1748 to 1753 (1961).

Compounds I are useful because they have pharmacological activity. They are useful as antihypertensives and diuretics. They are administered to mammals either orally or parenterally in daily doses of from 5 to 20 mg./kg. of body weight, e.g., for large mammals from 300' to 1200 milligrams per diern, preferably administered in doses of from 75 to 600 milligrams; a single daily oral dose is also acceptable.

For the above uses, the compounds may be combined with a pharmaceutically acceptable carrier, and such other conventional adjuvants, as may be necessary, and administered orally in such forms as tablets, capsules, elixirs, suspensions or solutions, or parenterally in such forms as injectable solutions, suspensions or emulsions. Furthermore, the compounds may be similarly administered in the form of their non-toxic pharmaceutically ac ceptable acid addition salts. Such salts possess the same order of activity as the free base, are readily prepared in conventional manner by reacting the base with the appropriate acid and accordingly are included within the scope of the invention. Representative of such salts are the mineral acid salts such as the hydrochloride, hydrobromide, sulfate, phosphate and the like and the organic acid salts such as the succinate, benzoate, acetate, maleate, p-toluenesulfonate, benzenesulfonate and the like.

For example, each of the pharmaceutically active compounds of this invention may be incorporated, for oral administration, in a tablet as the sole active ingredient. A typical tablet is constituted by from 1 to 3 percent binder, e.g., tragacanth; from 3 to 10 percent disintegrating agent, e.g., corn starch; from 2 to 10 percent lubricant, e.g., talcum; from 0.25 to 1.0 percent lubricant, e.g., magnesium stearate; and average dosage of active ingredient; and q.s. percent of filler, e.g., lactose; all percentages being by weight. Tablets are prepared according to standard tabletting techniques, which are wellknown in the art, employing the necessary amounts of conventional granulating liquids, e.g., alcohol SD-30 and purified water. An exemplary tabletting formulation for the instant active compounds is:

Parts Title compound of the example 75 Tragacanth 2 Lactose 14.5 Corn starch 5 Talcum 3 Magnesium stearate 0.5

Alcohol SD-30, purified water, q.s.

The title compound of the example is also useful as an appetite suppressant.

An example illustrative of this invention follows. Throughout this disclosure all temperatures are centigrade (room temperature is 20) and all percents and parts are by weight, unless specified otherwise. Parts by weight are related to parts by volume as a kilogram is related to a liter.

EXAMPLE 3-formamido-3,4-dihydro-4-oxo-pyrimido [-4,5-b]indole This example illustrates the preparation of a Compound I according to the reaction scheme presented above.

(a) 2-aminoindol-3-carboxylic acid hydrazide Dissolve parts of 2-aminoindo1e-3-carboxy1ic acid ethyl ester in 100 parts by volume of 95% anhydrous hydrazine and reflux the mixture for hours. Cool the mixture and evaporate under vacuum to obtain a resi due. Dissolve the residue in methanol and remove the residual hydrazine by evaporating under vacuum. Crystallize the residue from ethanol to obtain crude Compound a, then recrystallize from ethanol-chloroform (2:1) to obtain purified Compound a, melting point (M.P.) 201 to 205.

(b) 3-form amide-3,4-dihydro-4-ox0-pyrimido- [4,5 -b] indole Reflux a mixture of 10.4 parts of purified Compound a and 200 parts by volume of 98 to 100% formic acid for 15 hours. Dilute the reaction mixture with 400 parts by volume of water, to form a precipitate of crude title compound, which then separate by filtration and wash on the filter first with 200 parts by volume of water then 50 parts by volume of ethanol and finally 100 parts by volume of diethyl ether. Recrystallize from 500 parts by volume of ethanol-dioxane (1:1) to obtain the purified title compound, M.P. 312 to 315.

Following the procedure described in Step a of this example but replacing the 2-aminoindole-3-carboxylic acid ethyl ester with an equivalent amount of 4-chloro-2- l H I U A J wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy; and R is a member selected from the group consisting of a hydrogen atom, methyl, ethyl and propyl; and (B) a pharmaceutically acceptable acid addition salt of a compound of said formula.

2. The compound according to claim 1 wherein each of R and R is a hydrogen atom.

3. A compound of the formula:

wherein R is a member selected from the group consisting of a hydrogen atom, chloro and methoxy. 4. The compound according to claim 3 wherein R is a hydrogen atom.

References Cited UNITED STATES PATENTS 3,320,278 5/1967 Ruyle et a1. 260-32614 FOREIGN PATENTS 1,363,855 5/1964 France.

OTHER REFERENCES Magidson et al., Chem. Abstracts, vol. 64 (1966), col. 19634.

NICHOLAS S. RIZZO, Primary Examiner.

R. J. GALLAGHER, Assistant Examiner. 

